Lower urinary tract symptoms (LUTS) resulting from bladder outlet obstruction (BOO) remains one of the most commonly encountered disorders in urology, and can be secondary to fixed anatomical and/or functional causes (Steers et al, Voiding dysfunction: diagnosis, classification. and management, in Adult and Pediatric Urology; Third Edition, J. Y. Gillenwater. et al., Editors. 1996, Mosby-Year Book, Inc.: St. Louis. p. 1220-1325.). Causes of BOO include prostatic enlargement (benign or malignant), bladder neck contracture, urethral stricture, and meatal stricture (Steers et al, Voiding dysfunction: diagnosis, classification, and management, in Adult and Pediatric Urology; Third Edition, J. Y. Gillenwater, et al., Editors. 1996, Mosby-Year Book, Inc.: St. Louis. p. 1220-1325.). Symptoms associated with BOO typically fall into obstructive or irritative categories; obstructive symptoms include hesitancy, poor stream, prolonged urination, and feelings of incomplete emptying, while irritative symptoms consist of frequency, urgency. nocturia. and unstable bladder contractions. The bladder is functionally and anatomically divided into the detrusor (body and ventral base) and trigone (dorsal portion of base extending between the ureteral orifices and the bladder neck) (Zderic et al. Voiding function: relevant anatomy, physiology. pharmacology, and molecular aspects, in Adult and Pediatric Urology; Third Edition, J. Y. Gillenwater, et al., Editors. 1996, Mosby-Year Book, Inc.: St. Louis. p. 1159-1219), with distinct histology, histochemistry, and pharmacology. In contrast, the prostate and trigone have similar vascular supply, innervation, and receptor expression (Gosling et al. Detrusor morphology in relation to bladder outflow obstruction and instability, in Benign Prostatic Hypertrophy. F. Hinman, Editor. 1983, Springer-Verlag: Berlin. p. 666-71).
The physiology of LUTS secondary to benign prostatic hypertrophy (BPH) has two components: (1) a static component related to the increase in prostatic cellular mass and (2) a dynamic component related to variations in prostatic smooth muscle tone (Caine et al, Brit. J. Urol. 47:193-202 (1975)). Histologically BPH is characterized by glandular (epithelial) and stromal (fibromuscular) hyperplasia, with the latter being the dominant factor in the pathogenesis of clinically significant BPH (Shapiro et al, J. Urol. 147:1293-1297 (1992)). Therefore much attention has focused on the role of the sympathetic nervous system and α1-adrenergic receptors (α1ARs) in the dynamic component of BOO, leading to clinical studies of α1AR antagonists as agents to relieve outlet obstruction. These studies have found that α1AR antagonists relax prostatic smooth muscle, relieving obstructive symptoms (Chapple, Brit. J. Urol. 1:47-55 (1995), Caine, Urol. Clin. N. Am. 17:641-649 (1990), Kawabe and Niijima, Urol. Int. 42:280-284 (1987), Lepor et al, J. Urol. 148:1467-1474 (1992), Reuther and Aagaard, Urol. Int. 39:312-313 (1984), Matyus and Horvath. Med. Res. Rev. 17:523-535 (1997)). In addition, α1AR antagonists have been found to relieve the irritative bladder symptoms in men (most often associated with BPH) and women (Matyus and Horvath, Med. Res. Rev. 17:523-535 (1997), Serels and Stein, Neurourol. Urodyn. 17:31-36 (1998)). While it is logical to assume that elimination of BOO would relieve irritative symptoms, a number of recent studies suggest that the relationship between bladder irritability and outlet obstruction is not straightforward (Caine, Urol. Clin. N. Am. 17:641-649 (1990), Chapple and Smith, Brit. J. Urol. 73:117-123 (1994), Steers and De, J. Urol. 140:864-71 (1988), Steers et al, Am. J. Physiol. 266:R20 (1994)).
α1ARs are members of the larger family of G protein-coupled adrenergic receptors which mediate actions of the endogenous catecholamines norepinephrine (NE) and epinephrine, resulting in smooth muscle contraction. cDNAs encoding three distinct α1AR subtypes (α1a, α1b, α1d) have been cloned, expressed in cells, and resultant protein characterized pharmacologically (Schwinn et al, J. Pharmacol. Exper. Ther. 272:134-142 (1995), Hieble et al, Pharmacol. Rev. 47:267-70 (1995)). α1aARs predominate in prostate and bladder trigone (Price et al, J. Urol. 150:546-551 (1993)), and have been shown to be functionally important in mediating prostate smooth muscle contraction (Forray et al, Mol. Pharmacol. 45:703-708 (1994), Lepor et al., J. Pharmacol. Exper. Ther. 270:722-727 (1994)). In addition to the three cloned α1AR subtypes which have high affinity for the antagonist prazosin, a fourth type of α1AR with low affinity for prazosin (α1L) has been postulated (Muramatsu et al, Brit. J. Urol. 74:572-578 (1994)). In spite of initial evidence suggesting a role for the α1LAR in human prostate smooth muscle contraction (Ford et al, Mol. Pharmacol. 49:209-215 (1996)), more recent data suggests RS17053 (the compound used in these studies) detects a low affinity state of the α1aAR in tissues rather than a distinct α1LAR (Ford et al. Br. J. Pharmacol. 121:1127-1135 (1997)). Since non-selective α1AR antagonists currently used to treat BPH have undesirable side-effects including light headedness, dizziness, and asthenia (Carruthers. Drug Safety 11:12-20 (1994)), many investigators have suggested that α1aAR subtype selective antagonists might be beneficial in improving BPH-related symptoms via relieving BOO (Matyus and Horvath, Med. Res. Rev. 17:523-535 (1997), Hieble and Ruffolo, Jr., Exp. Opin. Invest. Drugs 6:367-387 (1997)). However, this approach does not take into account that irritative symptoms may persist in spite of relief of outlet obstruction (Hieble and Ruffolo, Jr., Exp. Opin. Invest. Drugs 6:367-387 (1997)).
Very little information exists regarding the role of α1ARs in human detrusor. One of the few studies addressing this issue suggests human bladder (dome) contains only α1aARs (Walden et al. J. Urol. 157:1032-1038 (1997)). However, since irritative bladder symptoms persist in some patients despite relief of BOO, nonselective α1AR antagonists may relieve the irritative effects of BPH through direct effects on bladder detrusor or other sites involved in micturation. The present invention results from the realization that human detrusor expresses two α1AR subtypes (α1d>α1a). This realization makes possible the identification of α1AR subtype selective antagonists that can be used to treat irritative symptoms.